JP2009030051A - Carbonate copolymer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a polymer having enhanced characteristics for forming a medical device and a coating of the medical device. <P>SOLUTION: A method includes a process of forming a copolymer by polymerizing at least one cyclic monomer under the presence of an aromatic cyclic carbonate, and a process of recovering the obtained copolymer. A copolymer is produced by the above method. A medical device, a drug delivering device, and a coating of the devices contain the above copolymer. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present disclosure is particularly useful in the manufacture of medical devices such as sutures, staples, clips, anastomosis rings, bone plates and screws, matrices for sustained and / or controlled release of pharmaceutically active ingredients, etc. A polymer composition is provided. In some embodiments, these polymer compositions can be utilized as coatings for medical devices.

  Polymers and copolymers of lactide and / or glycolide and / or related compounds, and surgical devices made therefrom are within the knowledge of one skilled in the art. In addition, other patents disclose surgical devices prepared from copolymers of lactide or glycolide and other monomers, including caprolactone or trimethylene carbonate. For example, U.S. Patent Nos. 5,099,086 and 5,037,028 disclose copolymers of epsilon-caprolactone and glycolide useful in making surgical articles, particularly surgical sutures. In addition, US Pat. No. 6,099,059 relates to the use of high molecular weight caprolactone polymers as coatings for surgical sutures, while US Pat. No. 4,057,096 is a triblock prepared by copolymerizing glycolide and trimethylene carbonate. A surgical article made from the copolymer is disclosed.

The properties of the bioabsorbable polymer can vary considerably depending on the nature and amount of the comonomer used (if present) and / or the polymerization procedure used in preparing the polymer. The selection of such polymers for use in the formation of medical devices and their coatings is dependent on the properties of the various polymers (physical properties such as the tensile strength of the polymer and the time until loss of strength and / or degradation occurs). Length etc.).
US Pat. No. 4,605,730 US Pat. No. 4,700,704 U.S. Pat. No. 4,624,256 US Pat. No. 4,429,080

  Although current medical devices and their coatings formed from bioabsorbable polymers may work satisfactorily, there is room for improvement with respect to polymers with enhanced properties for the formation of medical devices and medical device coatings.

In order to solve the above problems, the present invention provides, for example:
(Item 1)
A method,
Polymerizing at least one cyclic monomer in the presence of an aromatic cyclic carbonate to form a copolymer; and recovering the resulting copolymer;
Including the method.

(Item 2)
Item 2. The method according to Item 1, wherein the at least one cyclic monomer is selected from the group consisting of a cyclic ester and a cyclic carbonate.

(Item 3)
The at least one cyclic monomer is glycolide, L (−)-lactide, D (+)-lactide, meso-lactide, p-dioxanone, 1,4-dioxane-2-one, 1,5-dioxepane-2. The method of item 1, comprising a cyclic ester selected from the group consisting of -one, ε-caprolactone, δ-valerolactone, γ-butyrolactone, β-propiolactone, and combinations thereof.

(Item 4)
The at least one cyclic monomer is ethylene carbonate, trimethylene carbonate, dimethyl trimethylene carbonate, 3-ethyl-3-hydroxymethyl trimethylene carbonate, propylene carbonate, trimethylolpropane monocarbonate, 4,6-dimethyl-1, Item 2. The method according to Item 1, comprising a cyclic carbonate selected from the group consisting of 3-propylene carbonate, 2,2-dimethyltrimethylene carbonate, and 1,3-dioxepan-2-one, and combinations thereof.

(Item 5)
The aromatic cyclic carbonate has the formula

の芳香族環状カーボネートであり、該式において、Ｒは、ベンゼンを含む芳香族であり、Ｚは、ＣＯＯを含み、そしてｎは、約１〜約３０の数である、項目１に記載の方法。

A method according to item 1, wherein R is an aromatic comprising benzene, Z comprises COO, and n is a number from about 1 to about 30. .

(Item 6)
The aromatic cyclic carbonate has the formula

の芳香族環状カーボネートである、項目１に記載の方法。

The method according to Item 1, wherein the aromatic cyclic carbonate is.

(Item 7)
The aromatic cyclic carbonate has the formula

の芳香族環状カーボネートであり、該式において、ｍは、約１〜約３０の数である、項目１に記載の方法。

The method according to item 1, wherein m is a number from about 1 to about 30.

(Item 8)
The step of polymerizing the at least one cyclic monomer in the presence of the aromatic cyclic carbonate causes the cyclic monomer and the aromatic cyclic carbonate to reach a temperature of about 170 ° C. to about 185 ° C. for about 4 hours to about 6 Item 2. The method according to Item 1, comprising the step of heating over time.

(Item 9)
Polymerizing the at least one cyclic monomer in the presence of the aromatic cyclic carbonate, the cyclic monomer and the aromatic cyclic carbonate to a temperature of about 175 ° C. to about 180 ° C. for about 4.25 hours to The method of item 1, comprising the step of heating for about 4.75 hours.

(Item 10)
The method of item 1, further comprising heating the copolymer to a temperature of about 100 ° C. to about 120 ° C. for a time ranging from about 25 hours to about 35 hours.

(Item 11)
The method of item 1, further comprising heating the copolymer to a temperature of about 107 ° C. to about 113 ° C. for a time ranging from about 28 hours to about 32 hours.

(Item 12)
A copolymer produced by the method of item 1.

(Item 13)
formula

を有する、項目１に記載の方法によって生成されたコポリマーであって、該式において、
Ｗは、エステルおよびカーボネートからなる群より選択される環状モノマーから得られる誘導体であり、
Ａは、芳香族環状オリゴマーカーボネートから得られる芳香族カーボネート誘導体であり、
ｘは、約１〜約２００の数であり、そして
ｙは、約１〜約２００の数である、
コポリマー。

A copolymer produced by the method of item 1 having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of esters and carbonates;
A is an aromatic carbonate derivative obtained from an aromatic cyclic oligomeric carbonate,
x is a number from about 1 to about 200, and y is a number from about 1 to about 200.
Copolymer.

(Item 14)
W comprises about 15% to about 75% by weight of the total weight of the copolymer, and A comprises about 20% to about 75% by weight of the total weight of the copolymer.
Item 14. The copolymer according to item 13.

(Item 15)
formula

を有する、項目１に記載の方法によって生成されたコポリマーであって、該式において、
Ｗは、エステルおよびカーボネートからなる群より選択される環状モノマーから得られる誘導体であり、
ｘは、約１〜約２００の数であり、そして
ｙは、約１〜約２００の数である、
コポリマー。

A copolymer produced by the method of item 1 having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of esters and carbonates;
x is a number from about 1 to about 200, and y is a number from about 1 to about 200.
Copolymer.

(Item 16)
formula

を有する、項目１に記載の方法によって生成されたコポリマーであって、該式において、
Ｗは、エステルおよびカーボネートからなる群より選択される環状モノマーから得られる誘導体であり、
ｘは、約５０〜約１５０の数であり、そして
ｙは、約５０〜約１５０の数である、
コポリマー。

A copolymer produced by the method of item 1 having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of esters and carbonates;
x is a number from about 50 to about 150, and y is a number from about 50 to about 150.
Copolymer.

(Item 17)
A medical device comprising a copolymer produced by the method of item 1.

(Item 18)
A drug delivery device comprising a copolymer produced by the method of item 1.

(Item 19)
A coating for a medical device comprising a copolymer produced by the method of item 1.

(Item 20)
formula

を有するコポリマーであって、該式において、
Ｗは、環状エステルおよび環状カーボネートからなる群より選択される環状モノマーから得られる誘導体であり、
ｘは、約１〜約２００の数であり、
ｙは、約１〜約２００の数であり、そして
Ａは、式

A copolymer having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of cyclic esters and cyclic carbonates;
x is a number from about 1 to about 200;
y is a number from about 1 to about 200, and A is a formula

の芳香族環状オリゴマーカーボネートから得られる芳香族カーボネート誘導体であり、式（Ｉ）において、Ｒは、ベンゼンを含む芳香族であり、Ｚは、ＣＯＯを含み、そしてｎは、約１〜約３０の数である、
コポリマー。

An aromatic carbonate derivative obtained from an aromatic cyclic oligomeric carbonate of formula (I) wherein R is an aromatic containing benzene, Z is COO and n is from about 1 to about 30 Is a number,
Copolymer.

(Item 21)
W is glycolide, L (−)-lactide, D (+)-lactide, meso-lactide, p-dioxanone, 1,4-dioxan-2-one, 1,5-dioxepan-2-one, ε-caprolactone , Δ-valerolactone, γ-butyrolactone, β-propiolactone, ethylene carbonate, trimethylene carbonate, dimethyl trimethylene carbonate, 3-ethyl-3-hydroxymethyl trimethylene carbonate, propylene carbonate, trimethylolpropane monocarbonate, 4 A derivative obtained from a cyclic monomer selected from the group consisting of 1,6-dimethyl-1,3-propylene carbonate, 2,2-dimethyltrimethylene carbonate, and 1,3-dioxepane-2-one, and combinations thereof Yes, and A is Formula

からなる群より選択される芳香族環状カーボネートから得られる芳香族カーボネート誘導体であり、該式において、ｍは、約１〜約３０の数である、
項目２０に記載のコポリマー。

An aromatic carbonate derivative obtained from an aromatic cyclic carbonate selected from the group consisting of: wherein m is a number from about 1 to about 30.
Item 21. The copolymer according to item 20.

(Item 22)
Item 21. W comprises from about 15 wt% to about 75 wt% of the total weight of the copolymer, and A comprises from about 20 wt% to about 75 wt% of the total weight of the copolymer. Copolymer.

  Copolymer compositions containing cyclic monomers and aromatic cyclic carbonates are provided. The copolymer can be produced in some embodiments by a ring-opening polymerization reaction initiated by the aromatic cyclic carbonate. The resulting copolymer can be utilized in manufacturing coatings for medical devices, drug delivery devices, and / or medical devices.

(Summary)
Copolymer compositions are provided that contain a cyclic monomer and an aromatic cyclic carbonate. This copolymer can be produced in some embodiments by a ring-opening polymerization reaction initiated by an aromatic cyclic carbonate. In certain embodiments, the method for producing such a copolymer comprises polymerizing at least one cyclic monomer in the presence of an aromatic cyclic carbonate to form the copolymer, and recovering the resulting copolymer. Is included.

  In certain embodiments, the copolymers of the present disclosure have the formula

を有し得る。この式において、Ｗは、環状エステルおよび環状カーボネートを含む環状モノマーから得られる誘導体であり、ｘは、約１〜約２００の数であり、ｙは、約１〜約２００の数であり、そしてＡは、式

Can have. In this formula, W is a derivative obtained from a cyclic monomer including a cyclic ester and a cyclic carbonate, x is a number from about 1 to about 200, y is a number from about 1 to about 200, and A is the formula

の芳香族環状オリゴマーカーボネートから得られる芳香族カーボネート誘導体であり、この式において、Ｒは、ベンゼンを含む芳香族であり、Ｚは、ＣＯＯを含み、そしてｎは、約１〜約３０の数である。

Wherein R is an aromatic comprising benzene, Z comprises COO, and n is a number from about 1 to about 30 is there.

  The resulting copolymer can be utilized in manufacturing coatings for medical devices, drug delivery devices, and / or medical devices.

  The present invention provides polymers with enhanced properties for the formation of medical devices and medical device coatings.

(Detailed explanation)
The compositions described herein are useful for the formation of medical devices, drug delivery devices, and / or medical device coatings. These compositions contain a copolymer formed by polymerizing a cyclic monomer in the presence of a cyclic carbonate having an aromatic group in the ring. Suitable cyclic monomers for use in forming the copolymers of the present disclosure have desirable properties, including reasonable reaction rates under suitable reaction conditions. The resulting copolymers are biocompatible, making them suitable for the manufacture of medical devices and their coatings, and drug delivery devices.

  Copolymers prepared according to the present disclosure contain at least one cyclic monomer as the first component of the copolymer. Suitable cyclic monomers include, for example, cyclic esters such as lactones, and cyclic carbonates. Suitable cyclic esters can include cyclic esters having small rings (in some embodiments, 5-membered rings, in other embodiments, 6-membered rings, and in other embodiments, 7-membered rings). In some embodiments, a suitable cyclic ester can have a heteroatom (eg, oxygen) adjacent to the α-carbon. Suitable cyclic esters include glycolide, L (−)-lactide, D (+)-lactide, meso-lactide, p-dioxanone, 1,4-dioxane-2-one, 1,5-dioxepan-2-one , Ε-caprolactone, δ-valerolactone, γ-butyrolactone, β-propiolactone, and combinations thereof.

  Suitable cyclic carbonates include, for example, ethylene carbonate, trimethylene carbonate, dimethyl trimethylene carbonate, 3-ethyl-3-hydroxymethyl trimethylene carbonate, propylene carbonate, trimethylolpropane monocarbonate, 4,6-dimethyl-1, 3-propylene carbonate, 2,2-dimethyltrimethylene carbonate, 1,3-dioxepan-2-one, and combinations thereof.

  In certain embodiments, the copolymer of the present disclosure contains a cyclic carbonate having an aromatic group in its ring. Examples of the cyclic carbonate having an aromatic group include an oligomer cyclic carbonate having an aromatic group in the ring (sometimes referred to as “aromatic cyclic carbonate” and “aromatic cyclic oligomer carbonate” in this specification). And derivatives thereof. Examples of such aromatic cyclic oligomeric carbonates include, for example, Odian, “Principles of Polymerization”, 3rd edition, John Wiley & Sons, Inc. Those disclosed on pages 569-573, the entire disclosure of which is incorporated herein by reference.

  In some embodiments, the aromatic cyclic oligomeric carbonate has the formula

のものであり得、この式において、Ｒは、ベンゼンなどの芳香族基であり；Ｚは、ＣＯＯなどであり得；ｎは、約１〜約３０の数であり得；そしてこの環状カーボネートの残りの部分は、約１個〜約３０個、ある実施形態においては、約２個〜約１５個の炭素原子を有し得、そして例えば、ラクトン（ブチロラクトン、バレロラクトン、カプロラクトン、プロピオラクトンおよびこれらの組み合わせが挙げられる）ならびに他の環状エステル（例えば、ジオキサノン、グリコリド、ラクチド、ビスフェノールＡ、およびこれらの組み合わせ）などの環状エステルから誘導される環状カーボネートを含み得る。

In which R is an aromatic group such as benzene; Z can be COO or the like; n can be a number from about 1 to about 30; and the cyclic carbonate The remaining portion may have from about 1 to about 30, in some embodiments, from about 2 to about 15 carbon atoms and includes, for example, lactones (butyrolactone, valerolactone, caprolactone, propiolactone and And combinations thereof) as well as cyclic carbonates derived from cyclic esters such as other cyclic esters such as dioxanone, glycolide, lactide, bisphenol A, and combinations thereof.

  In some embodiments, the aromatic cyclic carbonate has the formula:

の芳香族環状カーボネートであり得る。

Aromatic cyclic carbonates.

  In other embodiments, the aromatic cyclic carbonate may include cyclic oligomeric carbonates derived from bisphenol A derivatives, including bisphenol A, 2,2'-bis (4-hydroxyphenyl) propane. Examples of such compounds include the following formula

の化合物が挙げられる。この式において、ｍは、約１〜約３０の数である。

The compound of this is mentioned. In this formula, m is a number from about 1 to about 30.

  The copolymers of the present disclosure can be formed by combining cyclic monomers and aromatic cyclic carbonates using any method or process within the purview of those skilled in the art. In certain embodiments, the copolymers of the present disclosure can be obtained by subjecting a cyclic monomer to a ring-opening polymerization reaction initiated by an aromatic cyclic carbonate. The result of such a polymerization reaction can include both ester and / or carbonate derivatives from cyclic monomers and aromatic carbonate derivatives from aromatic cyclic oligomeric carbonates. Thus, in some embodiments, the resulting copolymer has the formula:

のコポリマーであり得る。この式において、Ｗは、環状モノマーから得られる誘導体（ある実施形態において、エステルまたはカーボネート）であり；Ａは、芳香族環状オリゴマーカーボネートから得られる芳香族カーボネート誘導体であり；ｘは、約１〜約２００（ある実施形態において、約５０〜約１５０）の数であり、そしてｙは、約１〜約２００（ある実施形態において、約５０〜約１５０）の数である。

Of the copolymer. In this formula, W is a derivative derived from a cyclic monomer (in some embodiments, an ester or carbonate); A is an aromatic carbonate derivative derived from an aromatic cyclic oligomeric carbonate; The number is about 200 (in some embodiments, about 50 to about 150), and y is a number from about 1 to about 200 (in some embodiments, about 50 to about 150).

  In certain embodiments, when the aromatic cyclic oligomeric carbonate has the structure of Formula II above, the resulting copolymer has the following structure:

を有し得る。この式において、Ｗ、ｘ、およびｙは、上で定義されたとおりである。

Can have. In this formula, W, x, and y are as defined above.

  In other embodiments, when the aromatic cyclic oligomeric carbonate has the structure of Formula III above, the resulting copolymer has the following structure:

を有し得る。この式において、Ｗ、ｘ、およびｙは、上で定義されたとおりである。

Can have. In this formula, W, x, and y are as defined above.

  The resulting copolymer may be random, block or alternating. Of course, it should be understood that one or more cyclic monomers may be used to form the copolymers of the present disclosure. When the copolymer is a block copolymer, the copolymer may have any block configuration such as AB, ABA, ABAB, ABC, ABCBA, BABA, BACAB, ABCD.

  Methods for forming the copolymers of the present disclosure are within the knowledge of one of ordinary skill in the art and may vary depending on the cyclic monomers and aromatic cyclic oligomeric carbonates utilized to form the copolymers of the present disclosure. Standard reaction conditions may be utilized. Cyclic monomers and aromatic cyclic carbonates can be combined in any suitable amount and in any order to form the copolymers of the present disclosure. In some embodiments, cyclic monomers and aromatic cyclic oligomeric carbonates can be combined in the presence of a catalyst such as tin octoate, sometimes under an inert atmosphere such as nitrogen gas.

  In some cases, it may be desirable for the polymerization to be performed under reduced pressure (eg, at a pressure of less than about 1 Torr (about 133.3 Pa)). In some embodiments, the cyclic monomer and aromatic cyclic carbonate are combined at a suitable temperature of about 170 ° C. to about 185 ° C., in some embodiments, about 175 ° C. to about 180 ° C., and in some cases about It may be desirable to heat to a temperature of 178 ° C. These monomers can be polymerized over a suitable period of time from about 4 hours to about 6 hours, and in certain embodiments from about 4.25 hours to about 4.75 hours.

  After this time, a molten copolymer can be obtained. Although not required, in some embodiments, the copolymers of the present disclosure can be about 25 hours to about 35 hours to a temperature of about 100 ° C. to about 120 ° C., and in some embodiments about 107 ° C. to about 113 ° C., In certain embodiments, heating may be performed for a period of about 28 hours to about 32 hours for further heat treatment. In some cases, it may be desirable to perform this second heat treatment at reduced pressure, in certain embodiments, at a pressure of less than about 1 Torr (about 133.3 Pa).

  Derivatives derived from cyclic monomers (in some embodiments, esters or carbonates) can be up to about 75% by weight of the total weight of the copolymer of the present disclosure, and in some embodiments, about 15% of the total weight of the copolymer of the present disclosure. % To about 75% by weight, and in other embodiments, may comprise from about 30% to about 50% by weight of the total weight of the copolymer of the present disclosure. Accordingly, the aromatic carbonate derivative obtained from the aromatic cyclic oligomeric carbonate can be up to about 85% by weight of the total weight of the copolymer of the present disclosure, and in some embodiments from about 25% to about about% of the total weight of the copolymer of the present disclosure. 85% by weight, in other embodiments, may constitute from about 50% to about 70% by weight of the total weight of the copolymers of this disclosure.

  Furthermore, the copolymers of the present disclosure can be combined with other biocompatible polymers as long as the other biocompatible polymers do not undesirably interfere with the biodegradable properties of the copolymers of the present disclosure. Blends of the presently disclosed copolymers with such other polymers design the precise release profile desired for targeted drug delivery, or the precise rate of biodegradability desired for structural implants. In doing so, it can provide greater flexibility. Examples of such additional biocompatible polymers include other polycarbonates; polyesters; polyorthoesters; polyamides; polyurethanes; poly (iminocarbonates); polyanhydrides; and combinations thereof.

  In some embodiments, the copolymers of the present disclosure can be combined with a fatty acid component. This fatty acid component contains a fatty acid, a fatty acid salt, or a salt of a fatty acid ester. Suitable fatty acids may be saturated or unsaturated and include higher fatty acids having more than about 12 carbon atoms. Examples of suitable saturated fatty acids include, for example, stearic acid, palmitic acid, myristic acid and lauric acid. Examples of suitable unsaturated fatty acids include oleic acid, linoleic acid, and linolenic acid. In addition, esters of fatty acids such as sorbitan tristearate or hydrogenated castor oil can be used.

Suitable fatty acid salts, C ₆ or higher fatty acids (especially fatty acids having from about 12 to 22 carbon atoms) polyvalent metal ion salts, and mixtures thereof. Fatty acid salts may be useful in some embodiments of the present disclosure, including calcium, magnesium, barium, aluminum, and zinc salts of stearic, palmitic and oleic acids. Particularly useful salts include calcium stearate commercial "food grade", which is about one-third of the C ₁₆ fatty acid and two-thirds of the C ₁₈ fatty acids, as well as minor amounts of C ₁₄ fatty acids and C _It consists of a mixture of ₂₂ fatty acids.

  Suitable fatty acid esters that can be combined with the copolymers of the present disclosure include calcium, magnesium, aluminum, barium, or zinc salts of stearoyl lactate; calcium, magnesium, aluminum, barium, or palmitic acid lactate salts Zinc salt; calcium salt, magnesium salt, aluminum salt, barium salt, or zinc salt of oleyl lactate, commercially available from 2-lactic stearoyl calcium (eg, American Ingredients Co., Kansas City, MO. Under the trademark VERV). 2-lactic acid stearoyl calcium) is particularly useful. Other fatty acid ester salts that may be utilized include: stearoyl lithium lactate, stearoyl potassium lactate, stearoyl rubidium lactate, stearoyl cesium lactate, stearoyl francium lactate, palmityl sodium lactate, palmityl lithium lactate, palmityl potassium lactate, palmitic rubidium lactate , Palmitic cesium lactate, palmityl francium lactate, oleyl sodium lactate, oleyl lithium lactate, potassium oleyl lactate, oleyl rubidium lactate, oleyl cesium lactate, and oleyl francium lactate lactate.

  In some embodiments, it may be desirable to combine a copolymer of the present disclosure with a wax. Suitable waxes that can be utilized include polyethylene wax, ethylene copolymer wax, hydrogenated hydrocarbon wax, hydrogenated vegetable oil, beeswax, carnauba wax, paraffin, microcrystalline wax, canderia, spermaceti wax, and mixtures thereof.

  In other embodiments, omega-6 fatty acids, including arachidonic acid, can be combined with the copolymers of the present disclosure.

  In still further embodiments, phospholipids can be combined with the copolymers of the present disclosure. Suitable phospholipids include phosphatidylcholine (PC), monoacylphosphatidylcholine (MAPC), diacylphosphatidylcholine (DAPC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylglycerol (PG), Examples include, but are not limited to, plasmalogens, sphingomyelin, ceramide, sylatine, polymers having phospholipid groups, and derivatives thereof. In some embodiments, a copolymer having phosphorylcholine groups can be added to the composition of the present disclosure. These copolymers include, for example, 2-methacryloyloxyethyl phosphorylcholine and other monomers such as methacrylates (eg, butyl methacrylate, benzyl methacrylate, methacryloyloxyethyl phenylcarbamate, and phenylmethacryloyloxyethyl carbamate). A copolymer.

  In some embodiments, the copolymers of the present disclosure may also be combined with one or more bioactive agents and / or medical agents, which may be retained in the copolymers of the present disclosure, It may be released from the copolymer. As used herein, “medical agent” is used in its broadest sense and includes any substance or mixture of substances that have clinical use. As a result, the medical agent may or may not have pharmacological activity per se (eg, a dye).

  The amount of medical agent present depends on the particular medical agent selected, but in some embodiments, the amount used is about 0.01% by weight of the device or coating containing the copolymer of the present disclosure. % To about 10% by weight.

  Examples of classes of medical agents that can be combined or mixed with the copolymers of the present disclosure include antibacterial drugs, analgesics, antipyretics, anesthetics, antispasmodics, antihistamines, anti-inflammatory drugs, cardiovascular drugs, diagnostics Drugs, sympathomimetic drugs, cholinergic drugs, antimuscarinic drugs, antispasmodics, hormones, growth factors, growth factors, muscle relaxants, adrenergic neuron blockers, antitumor drugs, immunosuppressive drugs, gastrointestinal drugs, These include diuretics, steroids, polysaccharides, and enzymes. It is also contemplated that a combination of medical agents can be used.

  Suitable antibacterial agents that can be combined with the copolymers of the present disclosure include triclosan (also known as 2,4,4′-trichloro-2′-hydroxydiphenyl ether), chlorhexidine and its salts (chlorhexidine acetate, gluconic acid Chlorhexidine, chlorhexidine hydrochloride, and chlorhexidine sulfate), silver and its salts (silver acetate, silver benzoate, silver carbonate, silver citrate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, oxidation) Silver, silver palmitate, silver protein, and silver sulfadiazine), polymyxin, tetracycline, aminoglycosides (eg, tobramycin and gentamicin), rifampicin, bacitracin, neomycin, chloramphenicol, Conazole, quinolone (eg, oxophosphate, norfloxacin, nalidixic acid, pefloxacin, enoxacin and ciprofloxacin), penicillin (eg, oxacillin and piperacil), nonoxynol 9, fusidic acid, cephalosporin As well as combinations thereof. In addition, antimicrobial proteins and peptides (eg, bovine lactoferrin and lactoferricin B) can be included as medical agents in the blends or emulsions of this disclosure.

  Other medical agents that can be combined with the copolymers of the present disclosure include local anesthetics; non-steroidal anti-fertilizers; parasympathomimetic agents; psychotherapeutic agents; tranquilizers; decongestants; sedative hypnotics; Sympathomimetic drugs; vaccines; vitamins; antimalarial drugs; antimigraine drugs; antiparkinsonian drugs (eg L-dopa); antispasmodic drugs; anticholinergic drugs (eg oxybutynin); Bronchodilators; cardiovascular agents (eg, coronary vasodilators and nitroglycerin); alkaloids; analgesics; anesthetics (eg, codeine, dihydrocodeinone, meperidine, morphine, etc.); non-anesthetic agents (eg, salicylate, Aspirin, acetaminophen, d-propoxyphene, etc.); opioid receptor antagonists (eg Naltrexone and naloxone); anticancer agents; antispasmodics; antiemetics; antihistamines; Cytotoxic drugs; estrogen; antibacterial agents; antifungal agents; antiviral agents; anticoagulants; antispasmodic drugs; antidepressants; antihistamines;

  Other examples of suitable medical agents that can be combined with the copolymers of the present disclosure include viruses and cells, peptides (eg, luteinizing hormone-releasing hormone analogs (eg, goserelin and exendin)) and proteins, analogs, muteins As well as active fragments thereof (eg, immunoglobulins, antibodies, cytokines (eg, lymphokines, monokines, chemokines)), blood coagulation factors, hematopoietic factors, interleukins (IL-2, IL-3, IL-4, IL-6) ), Interferon (β-IFN, α-IFN and γ-IFN), erythropoietin, nuclease, tumor necrosis factor (eg, GCSF, GM-CSF, MCSF), insulin, enzyme (eg, superoxide) Zismuta , Tissue plasminogen activator), tumor suppressors, blood proteins, gonadotropins (eg, FSH, LH, CG, etc.), hormones and hormone analogs (eg, growth hormone, corticotropin and luteinizing hormone releasing hormone ( LHRH)), vaccines (eg, tumor antigens, bacterial antigens and viral antigens); somatostatins; antigens; blood clotting factors; growth factors or growth factors (eg, nerve growth factors, insulin-like growth factors); protein inhibitors, protein antagonists, And protein agonists; nucleic acids (eg, antisense molecules, DNA and RNA); oligonucleotides; and ribozymes.

  Imaging agents (eg, iodine or barium sulfate, or fluorine) can also be combined with the copolymers of the present disclosure to visualize surgical areas using imaging equipment (including X-ray, MRI, and CAT scans). Can make it possible.

  In addition, enzymes can be added to the copolymers of the present disclosure to increase the degradation rate of these copolymers. Suitable enzymes include, for example, peptide hydrolases (eg, elastase, cathepsin G, cathepsin E, cathepsin B, cathepsin H, cathepsin L, trypsin, pepsin, chymotrypsin, γ-glutamyltransferase (γ-GTP), etc.); Examples include hydrolases (eg, phosphorylase, neuraminidase, dextranase, amylase, lysozyme, oligosaccharase, etc.); oligonucleotide hydrolases (eg, alkaline phosphatase, endoribonuclease, endodeoxyribonuclease, etc.). In some embodiments, when an enzyme is added, the enzyme can be included in a liposome or microsphere to control the release rate of the enzyme, thereby degrading the biocompatible composition of the present disclosure. Control the speed. Methods for incorporating enzymes into liposomes and / or microspheres are known to those skilled in the art.

  In certain embodiments, surfactants (eg, phospholipid surfactants) that provide antimicrobial stability properties and assist in the dispersion of other materials in the copolymers of the present disclosure can also be added.

  As described above, the copolymers of the present disclosure can be used to form coatings for medical devices, drug delivery devices, or substrates (eg, medical devices).

  As a structural medical device, the copolymers of the present disclosure have physical properties with specific chemical, physical, and mechanical properties sufficient for the desired application that ultimately degrades into non-toxic residues in vivo. Provide a specific form.

  The copolymers of the present disclosure are non-toxic. As noted above, depending on their specific physical properties (mostly influenced by the nature of the cyclic monomers and aromatic cyclic carbonates from which these copolymers can be prepared), the copolymers herein are Can be used in the manufacture of all or part of various implantable medical devices and prostheses. Surgical and medical articles that can be prepared using the copolymers of the present disclosure include burn dressings; hernia patches; drug-added dressings; fascia substitutes; gauze, cloth, sheets for liver hemostasis , Felts or sponges; artificial implants or substitutes; bandages; orthopedic pins, clamps, screws, and plates; clips; staples; hooks, buttons, and snaps; bone substitutes (eg, mandibular prostheses); Intrauterine devices (eg, spermicidal devices); tubes or capillaries for drainage or testing; surgical instruments; vascular implants or supports; intervertebral discs; extracorporeal tubing for kidney and cardiopulmonary machines; artificial skin Catheters; scaffolds for tissue engineering applications; sutures; suture coatings and the like. When applied to a suture, the coating composition containing the copolymer herein yields a suture having appropriate lubricity, knot knot properties, and knot safety properties.

  In certain embodiments, the copolymer can also be melt processed using conventional extrusion or injection molding techniques, in combination with any necessary medical agents, or these products can be combined with a suitable solvent. And subsequently forming a device and subsequently removing the solvent by evaporation or extraction. For example, when the copolymers of the present disclosure are used to form medical devices, these devices can be made by injection molding at temperatures and pressures within the knowledge of one of ordinary skill in the art. Typically, the feed for an injection molding apparatus can be a melt blend of the copolymer of the present disclosure in pellet form. The copolymer should be sufficiently dry when injection molded in order to avoid hydrolysis during processing. After molding, the resulting surgical device prepared from the copolymer of the present disclosure can be packaged and sterilized by conventional procedures. In order to remove residual stresses and strains, it may be desirable to anneal these devices to stabilize the shape of the devices and to reduce or eliminate component defects. Annealing can include reheating the medical device to a temperature above its glass transition temperature (at which temperature the chain mobility is maximal), and then slowly cooling the device slowly. The procedures, conditions, and equipment for forming the polymer structure are within the knowledge of those skilled in the art.

  The copolymers of the present disclosure can also be formed into films and / or foams, which can then be applied to wounds (eg, cuts, deep wounds, ulcers and burns) to aid healing. Medical agents (eg, wound healing and antibacterial agents) can be incorporated to speed healing of damaged tissue. In this manner, various growth factors, growth factors, antibiotics and antifungal agents can be combined with the copolymers of the present disclosure.

  In other embodiments, the copolymers of the present disclosure can be applied as a coating to medical devices. Suitable medical devices that can be coated with the copolymers of the present disclosure include any of the medical devices described above. In certain embodiments, medical devices that can be coated with the copolymers of the present disclosure include surgical needles, staples, clips and other fasteners, drug delivery devices, stents, pins, screws, prosthetic devices, implantable devices, wounds Bandages, anastomosis rings, and fibrous surgical articles (eg, sutures, prosthetic ligaments, prosthetic tendons, woven meshes, gauze, bandages, growth matrices) and the like. The fibers coated with the composition of the present invention may be knitted or woven together with other fibers (either absorbent or non-absorbent) to form a mesh or fabric.

  The copolymers of the present disclosure can be applied as a coating to the substrate using any technique within the purview of those skilled in the art, optionally in combination with any of the above additives. When the copolymer of the present disclosure is used as a coating for a medical device, the coating can be formed using any known technique (eg, extrusion, molding and / or solvent casting). This copolymer may be used alone, blended with other absorbent compositions, or blended with non-absorbent ingredients.

  In one embodiment, the copolymer of the present disclosure can be applied as a coating by dissolving the composition in a solvent that is a non-solvent for any polymer device to which the coating is applied. The solution containing the copolymer of the present disclosure is then either immersed in the medical device in this solution, by passing the medical device through a brush or other applicator, or sprayed on the surface of the medical device. Can be applied to the medical device. Suitable solvents for use in dissolving the copolymers of the present disclosure include volatile solvents such as methylene chloride, acetone, hexafluoroisopropanol (HFIP), tetrahydrofuran (THF), combinations thereof, and the like. However, it is not limited to these. The medical device moistened with the coating solution can then be passed through or held in the drying oven for a time and temperature sufficient to vaporize and remove the solvent. If desired, the suture coating composition may optionally contain additional ingredients (eg, medical agents or similar additives as described above (dyes, antibiotics, preservatives, growth factors, growth factors, anti-tumor agents). Inflammatory agents and the like))).

  When the copolymer of the present disclosure is combined with any additive to be used as a coating, an appropriate amount of copolymer to be coated as a solution if both the copolymer and the additional material are soluble in the same solvent And any additives can be dissolved in the solvent and applied to the medical device. For example, the copolymer of the present disclosure can be solubilized in a dilute solution of a volatile organic solvent (eg, acetone, methanol, ethyl acetate or toluene), and then the article is immersed in the solution to irrigate the surface of the article. Can be coated. Evaporating the solvent at an elevated temperature, if necessary, leaves a copolymer and optional additive coating on the medical device.

  When applied as a solution, the amount of solvent utilized ranges from about 85% to about 99% by weight of the weight of the solution (including any additional medical agent or adjuvant) utilized to apply the copolymer of the present disclosure. %, In some embodiments, from about 90% to about 98% by weight. In some embodiments, the solvent may be present at about 95% by weight of the solution utilized to apply the copolymer of the present disclosure.

  While the copolymers herein can be applied to any type of medical device, the copolymers can be particularly useful as coatings for sutures. The amount of copolymer applied to the suture varies greatly depending on the structure of the suture (eg, monofilament or multifilament, the size of the suture, and the composition of the suture). For multifilament sutures, the number of filaments and the braid or twist hardness can also affect the amount of coating.

  The coating can be applied to both monofilament and multifilament braided sutures, which can also be bioabsorbable in some embodiments. Suitable bioabsorbable monomers and polymers utilized for sutures (including bioabsorbable braided sutures) include lactide, glycolide, trimethylene carbonate, ε-caprolactone, caprolactam, polyester, nylon, and the like. It is done. The coating is about 0.5% to about 15% (w / w) of the base suture substrate, and in some embodiments, about 1% to about 5% (w / w) of the base suture substrate. ). The thickness of the coating depends on a number of factors, but can typically be from a thickness of less than 1 micron to a thickness of a few millimeters.

  In other embodiments, the copolymers of the present disclosure and any additives are not completely miscible with each other, or are completely miscible with any solvent utilized to combine these copolymers and additives. If not, an emulsion can be formed and utilized by any means known to those skilled in the art to form medical devices (including drug delivery devices) or coatings for medical devices. For example, if a medical agent is combined with a copolymer of the present disclosure but is not compatible with the copolymer, the medical agent can be placed in a solution and the copolymer of the present disclosure can be placed in another solution; These two solutions are then combined to form an emulsion or suspension. A biocompatible dispersant in the form of a surfactant, emulsifier or stabilizer can be added to the blend to assist in dispersing the medical agent throughout the copolymer of the present disclosure.

  An adjuvant may be added to stabilize or protect the copolymer. Such adjuvants include non-ionic surfactants, including alcohol ethoxylates, glycerol esters, polyoxyethylene esters, and glycol esters of fatty acids. Preferred nonionic surfactants are glycerol esters of stearic acid, oleic acid, and / or lauric acid, and ethylene glycol and / or diethylene glycol esters of fatty acids.

  The copolymers of the present disclosure, when utilized as a coating for a medical device, can improve the surface properties of the device (eg, cell and protein adhesion, lubricity, drug delivery, protein or DNA delivery, etc.). When used as a coating, the copolymers of the present disclosure are particularly useful in bacterial adhesion / colony formation, preventing infection caused or exacerbated by the device itself, and improving the handling properties of the device. possible.

  In other embodiments, particularly when the copolymers of the present disclosure are utilized as a drug delivery device to deliver medical agents, by processes such as ball mills, disk mills, sand mills, wearers, rotor stator mixers, sonication, etc. It may be desirable to mix this medical agent with the copolymer of the present disclosure. In other embodiments, the copolymer and any optional additives can be melt blended and used to form or coat a medical device. Other methods for making and using the copolymers of the present disclosure will be readily apparent to those skilled in the art.

  When a medical agent is combined with a copolymer of the present disclosure, the copolymer of the present disclosure provides a site-specific release of the medical drug (this release can be immediate release, delayed release or sustained release). Can be utilized as a drug delivery device to provide Immediate release systems provide drug doses immediately. The delayed release system provides repeated intermittent dosing of the drug. The sustained release system should achieve a slow release of drug over an extended period of time and maintain a therapeutically effective concentration of drug at the target site. The medical drugs that are mixed with the copolymers herein will typically degrade these copolymers from medical devices formed from the copolymers herein and / or any coatings formed from these copolymers. Prolonged release or sustained release treatment is provided by diffusion.

  It will be appreciated that the features and functions disclosed above, as well as various other features and functions, or alternatives thereof, may desirably be combined in many other different systems or applications. Also, alternatives, modifications, variations or improvements that are not currently anticipated or anticipated may be made later by those skilled in the art and are also intended to be encompassed by the appended claims. . Unless specifically stated in the claims, the steps or components of a claim may be described herein or otherwise with respect to any particular order, number, position, size, shape, angle, color, or material. It should not be suggested or expressed by any claims.

Claims (22)

A method,
Polymerizing at least one cyclic monomer in the presence of an aromatic cyclic carbonate to form a copolymer; and recovering the resulting copolymer;
Including the method. The method of claim 1, wherein the at least one cyclic monomer is selected from the group consisting of cyclic esters and cyclic carbonates. The at least one cyclic monomer is glycolide, L (−)-lactide, D (+)-lactide, meso-lactide, p-dioxanone, 1,4-dioxane-2-one, 1,5-dioxepane-2. The method of claim 1, comprising a cyclic ester selected from the group consisting of —one, ε-caprolactone, δ-valerolactone, γ-butyrolactone, β-propiolactone, and combinations thereof. The at least one cyclic monomer is ethylene carbonate, trimethylene carbonate, dimethyl trimethylene carbonate, 3-ethyl-3-hydroxymethyl trimethylene carbonate, propylene carbonate, trimethylolpropane monocarbonate, 4,6-dimethyl-1, The method of claim 1, comprising a cyclic carbonate selected from the group consisting of 3-propylene carbonate, 2,2-dimethyltrimethylene carbonate, and 1,3-dioxepan-2-one, and combinations thereof. The aromatic cyclic carbonate has the formula

The aromatic cyclic carbonate of claim 1, wherein R is an aromatic comprising benzene, Z comprises COO, and n is a number from about 1 to about 30. Method. The aromatic cyclic carbonate has the formula

The method according to claim 1, which is an aromatic cyclic carbonate. The aromatic cyclic carbonate has the formula

The method of claim 1, wherein m is a number from about 1 to about 30. Polymerizing the at least one cyclic monomer in the presence of the aromatic cyclic carbonate, the cyclic monomer and the aromatic cyclic carbonate to a temperature of about 170 ° C. to about 185 ° C. for about 4 hours to about 6; The method of claim 1, comprising heating over time. Polymerizing the at least one cyclic monomer in the presence of the aromatic cyclic carbonate, the cyclic monomer and the aromatic cyclic carbonate to a temperature of about 175 ° C. to about 180 ° C. for about 4.25 hours to The method of claim 1, comprising heating for about 4.75 hours. The method of claim 1, further comprising heating the copolymer to a temperature of about 100 ° C. to about 120 ° C. for a time ranging from about 25 hours to about 35 hours. The method of claim 1, further comprising heating the copolymer to a temperature of from about 107 ° C. to about 113 ° C. for a time ranging from about 28 hours to about 32 hours. A copolymer produced by the method of claim 1. formula

A copolymer produced by the process of claim 1 having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of esters and carbonates;
A is an aromatic carbonate derivative obtained from an aromatic cyclic oligomeric carbonate,
x is a number from about 1 to about 200, and y is a number from about 1 to about 200.
Copolymer. W comprises about 15% to about 75% by weight of the total weight of the copolymer, and A comprises about 20% to about 75% by weight of the total weight of the copolymer.
The copolymer according to claim 13. formula

A copolymer produced by the process of claim 1 having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of esters and carbonates;
x is a number from about 1 to about 200, and y is a number from about 1 to about 200.
Copolymer. formula

A copolymer produced by the process of claim 1 having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of esters and carbonates;
x is a number from about 50 to about 150, and y is a number from about 50 to about 150.
Copolymer. A medical device containing a copolymer produced by the method of claim 1. A drug delivery device comprising a copolymer produced by the method of claim 1. A coating for a medical device comprising a copolymer produced by the method of claim 1. formula

A copolymer having the formula:
W is a derivative obtained from a cyclic monomer selected from the group consisting of cyclic esters and cyclic carbonates;
x is a number from about 1 to about 200;
y is a number from about 1 to about 200, and A is a formula

An aromatic carbonate derivative obtained from an aromatic cyclic oligomeric carbonate of formula (I) wherein R is an aromatic containing benzene, Z is COO and n is from about 1 to about 30 Is a number,
Copolymer. W is glycolide, L (−)-lactide, D (+)-lactide, meso-lactide, p-dioxanone, 1,4-dioxan-2-one, 1,5-dioxepan-2-one, ε-caprolactone , Δ-valerolactone, γ-butyrolactone, β-propiolactone, ethylene carbonate, trimethylene carbonate, dimethyl trimethylene carbonate, 3-ethyl-3-hydroxymethyl trimethylene carbonate, propylene carbonate, trimethylolpropane monocarbonate, 4 A derivative obtained from a cyclic monomer selected from the group consisting of 1,6-dimethyl-1,3-propylene carbonate, 2,2-dimethyltrimethylene carbonate, and 1,3-dioxepane-2-one, and combinations thereof Yes, and A is Formula

An aromatic carbonate derivative obtained from an aromatic cyclic carbonate selected from the group consisting of: wherein m is a number from about 1 to about 30.
21. The copolymer of claim 20. 21. W comprises from about 15% to about 75% by weight of the total weight of the copolymer, and A comprises from about 20% to about 75% by weight of the total weight of the copolymer. Copolymer.